1-151909386-G-A

Variant names:

• chr1-151909386-G-A
• rs929655212
• NM_053055.5:c.73C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053055.5(THEM4):​c.73C>T​(p.Pro25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000739 in 1,353,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P25L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: THEM4 NM_053055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0740

Genes affected

THEM4 (HGNC:17947): (thioesterase superfamily member 4) Protein kinase B (PKB) is a major downstream target of receptor tyrosine kinases that signal via phosphatidylinositol 3-kinase. Upon cell stimulation, PKB is translocated to the plasma membrane, where it is phosphorylated in the C-terminal regulatory domain. The protein encoded by this gene negatively regulates PKB activity by inhibiting phosphorylation. Transcription of this gene is commonly downregulated in glioblastomas. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06431788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEM4	NM_053055.5	c.73C>T	p.Pro25Ser	missense_variant	Exon 1 of 6	ENST00000368814.8	NP_444283.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THEM4	ENST00000368814.8	c.73C>T	p.Pro25Ser	missense_variant	Exon 1 of 6	1	NM_053055.5	ENSP00000357804.3
THEM4	ENST00000471464.5	n.73C>T		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000431288.1
THEM4	ENST00000489410.1	c.73C>T	p.Pro25Ser	missense_variant	Exon 1 of 2	2		ENSP00000433304.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000739 AC: 10 AN: 1353442 Hom.: 0 Cov.: 29 AF XY: 0.00000899 AC XY: 6 AN XY: 667608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000938

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73C>T (p.P25S) alteration is located in exon 1 (coding exon 1) of the THEM4 gene. This alteration results from a C to T substitution at nucleotide position 73, causing the proline (P) at amino acid position 25 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.1
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.012
Sift	Benign	0.20	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.14	B;.
Vest4		0.052
MutPred		0.18		Gain of phosphorylation at P25 (P = 0.0013);Gain of phosphorylation at P25 (P = 0.0013);
MVP		0.040
MPC		0.11
ClinPred		0.085	T
GERP RS		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.030
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs929655212; hg19: chr1-151881862;